In recent years, as a result of an increase in persons of advanced age and also of changes in daily eating habits to the food of European and American style containing high calories and high cholesterol due to upgrade of the standard of living, there has been a rapid increase in hyperlipemia and arteriosclerotic diseases caused thereby and that is one of the social problems. The pharmacotherapy for hyperlipemia and arteriosclerosis up to now has mostly given its priority to reduce the lipid content in blood which is a cause thereof and has not been a therapy where arteriosclerotic focus per se is a target.
Acyl coenzyme A cholesterol acyltransferase (ACAT) is an enzyme which catalyzes the synthesis of cholesterol ester from cholesterol and plays an important role in metabolism and absorption in digestive organs of cholesterol. It is believed that inhibition of ACAT enzyme which esterifies free cholesterol in epithelial cells of small intestine results in inhibition of absorption of cholesterol from intestinal tract, that inhibition of production of cholesterol ester in liver due to ACAT inhibition suppresses the secretion of very low-density lipoprotein (VLDL) from liver into blood and that, as a result thereof, a decrease in cholesterol in blood is resulted. Many of ACAT inhibitors until now have been those which act the ACAT enzyme in small intestine and liver whereby a decrease in cholesterol in blood is expected as antihyperlipemic agents.
For example, 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide and N′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-yl thio)pentyl]-N-heptylurea are described as ACAT inhibitors in the U.S. Pat. No. 4,716,175 and the European Patent No. 372,445, respectively. However, many ACAT inhibitors up to now give a priority on lowering of cholesterol in blood as antihyperlipemic agents and, due to administration in large doses for achieving the action, many side effects such as intestinal bleeding, intestinal disturbance, diarrhea and hepatic disturbance occurred which made their clinical development difficult.
Incidentally, arteriosclerosis is a lesion characterized by thickening of intima and accumulation of lipid in blood vessel and, according to the recent studies, suppression of foaming of macrophage playing a central role in formation of arteriosclerotic lesion is expected to achieve an involution of arteriosclerotic lesion itself. Foam cells (cholesterol ester is stored in the cells as fat droplets) derived from macrophage are in focus of pultaceous arteriosclerosis and it has been said that this foaming of macrophage is closely related to the progress of the focus. It is also reported that the ACAT activity on the blood vessel wall of focus site of arteriosclerosis is high and the cholesterol is accumulated on the blood vessel wall (Gillies, P. J., et al.: Exp. Mole. Pathol., 44, 329-339(1986)).
Inhibition of esterification of cholesterol by an ACAT inhibitor produces free cholesterol in cells and this is then taken out by a high-density lipoprotein (HDL) followed by being transmitted to liver (reverse transmission) to be metabolized and, accordingly, suppression of accumulation of cholesterol at the focus site is expected. It is believed that, as a result thereof, a direct antiarteriosclerotic action is achieved. It is reported that there are two types of ACAT—one is present in small intestine and another is present on blood vessel wall (Kinnunen, P. M., et al.: Biochemistry, 27, 7344-7350(1988)) although many investigations on ACAT inhibitors until now have been conducted using enzymes which are those of a type existing in small intestine and liver (Tomoda, H., et al: J. Antibiotics, 47, 148-153(1994)). Having an idea that the drug which selectively inhibits the ACAT enzyme of a type existing in blood vessel wall can be a therapeutic agent for arteriosclerosis having less side effect, the present inventors have conducted synthesis and investigation on such an inhibitor, found that the compounds represented by the following formula. (A) selectively inhibit the ACAT enzyme and filed patent applications (refer to the specifications of the Japanese Patent Applications Hei-09/88660 and Hei-09/90146). [In the formula, A, Ar, X and Y have the same meanings as those defined for the above-mentioned formula (I) of the present invention; Z′ is Z or —CR4′R5′—Z— (where Z has the same meaning as that defined for the above-mentioned formula (I) of the present invention and R4′ and R5′ are same or different and are hydrogen atom, lower alkyl group or lower alkoxy group); and n′ is an integer of from 0 to 15.]
However, those compounds are highly liposoluble and, therefore, they have disadvantages that oral absorption is not good and that duration in serum is short.
Accordingly, there has been a demand for developing the compounds where oral absorption is improved and a high drug concentration in serum is maintained for long time.